Background: Many patients with non-small-cell lung cancer (NSCLC) do not benefit from first-line treatment with immune checkpoint inhibitors (ICI) alone or in combination with chemotherapy due to resistance or toxicity. In NSCLC, significant research has been undertaken to provide prognostic markers for single agent immune checkpoint inhibitor therapy. Co-alterations in TP53, STK11/LKB1 and KRAS have a low reported prevalence in NSCLC, however, potentially may represent a distinct molecular subtype of NSCLC that conveys primary resistance to single-agent ICI. Data continues to accumulate regarding resistance mechanisms to ICI, but limited data exists exploring these alterations and the corresponding survival outcomes in patients that receive chemoimmunotherapy. The primary objective of this study was to assess the association between alterations and co-alterations in STK11/LKB1 and survival outcomes in patients with NSCLC receiving chemo-immunotherapy. Methods: This was a retrospective study of patients ≥18 years old who had completed NGS testing and had a diagnosis of non-small-cell lung cancer that received chemoimmunotherapy from January 2016 to November 2022. NGS reports were reviewed to assess the status of STK11/LKB1, KRAS, KEAP1, and TP53 alterations. Additional markers assessed were PD-L1 status, TPS, CPS, TMB, and MSI if available. Results: Sixty-five patients were identified who had received chemoimmunotherapy for NSCLC, had NGS testing results, and were considered to be evaluable for retrospective review. Four patients were identified with co-altered KRAS, STK11, and TP53, and this alone was not significant for PFS (p= 0.48) or OS (p = 0.52) compared to patients without the alterations, however patients with the co-alterations and a positive PD-L1 showed an improvement in PFS (p =0.053). Patients with altered STK11, including those classified as VUS, had a poorer OS (p = 0.088). Our analysis also showed that PD-L1 negative patients had poorer OS (p = 0.088). Conclusions: The addition of chemotherapy to ICI may overcome resistance previously described in NSCLC patients with co-alterations in KRAS, STK11, and TP53, who received single-agent ICI and these genomic findings should not deter from the use of chemoimmunotherapy based on our limited experience. Patients with alterations in STK11 did have poorer outcomes overall, which is in line with previously published data describing STK11 as a poor prognostic marker in NSCLC. STK11 alterations have previously been described to be associated with PD-L1 negativity which may explain, at least in part, the poorer responses in the STK11 mutated subgroup.